The first known compounds with a bis-indole skeleton were alkaloids occuring in the Vinca rosea L plant, from which first vinblastine (VLB) (see U.S. Pat. No. 3,097,137) and then vincristine (VCR) and leurosine (Leu; see U.S. Pat. Nos. 3,205,220 and 3,370,570) were isolated. Since some of these alkaloids showed excellent anti-tumor activity, several synthetically modified derivatives were prepared.
The known indole-dihydroindole compounds successfully applied in tumor therapy are shown in formula (I) ##STR1##
Formula (I) covers two groups of known anti-tumor agents, in one group R.sup.1 stands for a methyl, and in the other one R.sup.1 stands for a formyl group.
Thus, in the first case the meaning of the substituents is as follows:
R.sup.1 represents a methyl group, PA0 R.sup.2 is hydrogen, PA0 R.sup.3 is a hydroxyl group, or PA0 R.sup.2 and R.sup.3 form together a valence bond, PA0 R.sup.4 is a hydroxyl or an acetoxy group, and PA0 R.sup.5 stands for a methoxy or an amino group. PA0 R.sup.1 represents a formyl group, PA0 R.sup.2 is hydrogen and PA0 R.sup.3 is hydroxyl, or PA0 R.sup.2 and R.sup.3 form together an epoxy group, PA0 R.sup.4 represents hydrogen or an acetoxy group and PA0 R.sup.5 is methoxy. PA0 R.sup.1 stands for a methyl group are as follows: vinblastine (VLB), corresponding to formula (I), when PA0 leurosidine, corresponding to formula (I), when PA0 15',20'-anhydro-vinblastine, corresponding to formula (I), when PA0 vindesine, corresponding to formula (I), when PA0 R.sup.1 represents a formyl group, are as follows: vincristine (VCR), corresponding to formula (I), when PA0 N-desmethyl-N-formyl-leurosine, corresponding to formula (I), when PA0 17-desacetoxy-vincristine, corresponding to formula (I), when PA0 15',20'-anhydro-vincristine, corresponding to formula (I), when
In the other case the definition of the substituents is as follows:
Preferred compounds covered by formula (I), wherein
R.sup.2 is hydrogen, PA1 R.sup.3 is hydroxyl, PA1 R.sup.4 is acetoxy, PA1 R.sup.5 is methoxy, and in the position 20' of the skeleton the hydroxy has .beta.-, and the ethyl group has .alpha.-configuration; PA1 R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the same meaning as in the case of VLB, but in the position 20' of the skeleton the hydroxyl has .alpha.-, and the ethyl group has .beta.-configuration; PA1 R.sup.2 and R.sup.3 form together a valence bond, PA1 R.sup.4 is acetoxy, and PA1 R.sup.5 is a methoxy group; and PA1 R.sup.2 is hydrogen, PA1 R.sup.3 is hydroxyl, PA1 R.sup.4 is hydroxyl, and PA1 R.sup.5 is an amino group, and in the position 20' the hydroxyl has .beta.-, and the ethyl group has .alpha.-configuration. PA1 R.sup.2 is hydrogen, PA1 R.sup.3 is hydroxyl, PA1 R.sup.4 is acetoxy, and PA1 R.sup.5 is a methoxy group, and in position 20' the hydroxy has .beta.- and the ethyl group has .alpha.-configuration; PA1 R.sup.2 and R.sup.3 form together an .alpha.--.alpha. epoxy bridge, PA1 R.sup.4 is acetoxy and PA1 R.sup.5 is a methoxy group, and the ethyl group in the position 20' has .beta.-configuration; PA1 R.sup.4 is a hydrogen, and the other substituents are the same as in the case of VCR; and PA1 R.sup.2 and R.sup.3 form together a valence bond, PA1 R.sup.4 is acetoxy and PA1 R.sup.5 is a methoxy group.
Preferred compounds covered by formula (I),
wherein
Bis-indole compounds are generally administered intravenously to patients suffering from neoplastic disease. For this purpose the active compounds should be brought into a stable solution form (i.e. injectable solution or infusion) which is directly injectable to the patients. However, in consequence of the insufficient stability of the dimer-indole compounds in gaseous solutions, until quite recently there was slight hope of having a directly utilizable formulation. The three bis-indole compounds, i.e. the vincristine, vinblastine and vindesine customarily used in clinical practice were available in two separate ampoules, one containing the lyophilized active ingredient (power ampoule) and the other one containing the sterile solvent (solvent ampoule) to dissolve the active component before use. This two-ampoule package, however, has several drawbacks. Firstly, the lyophilization is expensive, secondly the dissolution of each lyophilized sample should be carried out according to approved sterility and pyrogen-free standards to avoid risks in administration.
An improved process for the formulation of vinca dimers is disclosed in Belgian patent specification No. 897,280. According to said process, aqueous medical compositions containing a vinca dimer are prepared by dissolving a pharmaceutically acceptable salt of a vinca dimer and adding to the solution a polyol, and acetate buffer to maintain the pH of the solution at a value from 3 to 5, and a bacteriostatic agent. There are no storage-stability tests described, it is simply stated that 94-99% of the original active ingredient content are present after a 9-month storage period if the samples are stored at 5.degree. C. In the meantime a one-ampoule vincristine composition was put on the market for which at 5.degree. C. storage temperature a one year storage stability was guaranteed.